从测序数据中识别癌症驱动基因对于加深我们对肿瘤生物学的理解和扩大靶向治疗选择至关重要。然而，除了最常见的改变基因之外，其他突变对癌症获得的贡献机制仍未得到充分研究。利用最大的亚洲肺腺癌 (LUAD) 队列 (n = 302) 的全外显子组测序，我们现在对新型驱动程序 PARP4 的机制作用进行功能评估。体外和体内致瘤性测定用于研究功能PARP4 缺失和突变对多种肺癌细胞系的影响。通过定量质谱法进行相互作用组学分析，以确定 PARP4 的相互作用伙伴。来自细胞系和患者肿瘤的转录组数据用于研究剪接改变。PARP4 缺失或突变 (I1039T) 促进 KRAS 或 EGFR 驱动的肺癌细胞的致瘤性。 PARP4 通常与之相关的穹窿复合体的破坏不会改变致瘤性，表明 PARP4 的肿瘤抑制活性是独立介导的。剪接调节因子 hnRNPM 是一种潜在的新型 PARP4 相互作用伴侣，其缺失同样会促进肿瘤形成。 hnRNPM 丢失导致剪接扰动，具有内含子剪接失调的倾向，这在 PARP4 敲低细胞和 PARP4 拷贝数丢失的 LUAD 队列患者中也类似地观察到。 PARP4 是肺腺癌的一种新型调节剂，其肿瘤抑制活性不介导通过穹窿复合体，与传统认为的不同，但与其新颖的相互作用伙伴 hnRNPM 相关，因此表明剪接失调在 LUAD 肿瘤发生中的作用。© 2024。作者。

The identification of cancer driver genes from sequencing data has been crucial in deepening our understanding of tumor biology and expanding targeted therapy options. However, apart from the most commonly altered genes, the mechanisms underlying the contribution of other mutations to cancer acquisition remain understudied. Leveraging on our whole-exome sequencing of the largest Asian lung adenocarcinoma (LUAD) cohort (n = 302), we now functionally assess the mechanistic role of a novel driver, PARP4.In vitro and in vivo tumorigenicity assays were used to study the functional effects of PARP4 loss and mutation in multiple lung cancer cell lines. Interactomics analysis by quantitative mass spectrometry was conducted to identify PARP4's interaction partners. Transcriptomic data from cell lines and patient tumors were used to investigate splicing alterations.PARP4 depletion or mutation (I1039T) promotes the tumorigenicity of KRAS- or EGFR-driven lung cancer cells. Disruption of the vault complex, with which PARP4 is commonly associated, did not alter tumorigenicity, indicating that PARP4's tumor suppressive activity is mediated independently. The splicing regulator hnRNPM is a potentially novel PARP4 interaction partner, the loss of which likewise promotes tumor formation. hnRNPM loss results in splicing perturbations, with a propensity for dysregulated intronic splicing that was similarly observed in PARP4 knockdown cells and in LUAD cohort patients with PARP4 copy number loss.PARP4 is a novel modulator of lung adenocarcinoma, where its tumor suppressive activity is mediated not through the vault complex-unlike conventionally thought, but in association with its novel interaction partner hnRNPM, thus suggesting a role for splicing dysregulation in LUAD tumorigenesis.© 2024. The Author(s).